Wellcome Trust Sanger Institute

About: Wellcome Trust Sanger Institute is a nonprofit organization based out in Cambridge, United Kingdom. It is known for research contribution in the topics: Population & Genome. The organization has 4009 authors who have published 9671 publications receiving 1224479 citations.

Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer

Abstract: Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene.

Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index.

Abstract: We propose a method (GREML-LDMS) to estimate heritability for human complex traits in unrelated individuals using whole-genome sequencing data. We demonstrate using simulations based on whole-genome sequencing data that ∼97% and ∼68% of variation at common and rare variants, respectively, can be captured by imputation. Using the GREML-LDMS method, we estimate from 44,126 unrelated individuals that all ∼17 million imputed variants explain 56% (standard error (s.e.) = 2.3%) of variance for height and 27% (s.e. = 2.5%) of variance for body mass index (BMI), and we find evidence that height- and BMI-associated variants have been under natural selection. Considering the imperfect tagging of imputation and potential overestimation of heritability from previous family-based studies, heritability is likely to be 60-70% for height and 30-40% for BMI. Therefore, the missing heritability is small for both traits. For further discovery of genes associated with complex traits, a study design with SNP arrays followed by imputation is more cost-effective than whole-genome sequencing at current prices.

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma

Abstract: Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment.

Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding

Abstract: Transcription factors (TFs) direct gene expression by binding to DNA regulatory regions. To explore the evolution of gene regulation, we used chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) to determine experimentally the genome-wide occupancy of two TFs, CCAAT/enhancer-binding protein alpha and hepatocyte nuclear factor 4 alpha, in the livers of five vertebrates. Although each TF displays highly conserved DNA binding preferences, most binding is species-specific, and aligned binding events present in all five species are rare. Regions near genes with expression levels that are dependent on a TF are often bound by the TF in multiple species yet show no enhanced DNA sequence constraint. Binding divergence between species can be largely explained by sequence changes to the bound motifs. Among the binding events lost in one lineage, only half are recovered by another binding event within 10 kilobases. Our results reveal large interspecies differences in transcriptional regulation and provide insight into regulatory evolution.

Genome sequence, comparative analysis, and population genetics of the domestic horse.

Abstract: We report a high-quality draft sequence of the genome of the horse (Equus caballus). The genome is relatively repetitive but has little segmental duplication. Chromosomes appear to have undergone few historical rearrangements: 53% of equine chromosomes show conserved synteny to a single human chromosome. Equine chromosome 11 is shown to have an evolutionary new centromere devoid of centromeric satellite DNA, suggesting that centromeric function may arise before satellite repeat accumulation. Linkage disequilibrium, showing the influences of early domestication of large herds of female horses, is intermediate in length between dog and human, and there is long-range haplotype sharing among breeds.